The broad long term objectives of this research are to use a unique 3-D computer model to improve the timing and type of treatment offered to patients with mitral valve regurgitation, and to assess whether there is a role for earlier valve repair in selected etiologies. As the valve is affected by disease, the functional anatomy is often altered, the valve becomes regurgitant, and the normal distribution of mechanical stresses is disrupted. It is the central hypothesis of this application that mitral valve regurgitation, itself, induces structural changes and alters mechanical function. The clinical implication of this hypothesis is that the longer a valve is regurgitant, the more disrupted will be the tissue and the less likely that a surgical repair would be successful. The applicants proposed to test several aspects of this theory and will delineate the mechanisms that contribute to this process, in a three part approach. In Part One, they proposed to assess whether regurgitation induces structural change. Experimental sheep models will be used in which mitral regurgitation is created either by papillary muscle ischemia, or by disruption of the chordae tendineae. After 4, 8, or 16 weeks of regurgitation, the valves will be evaluated for the amount of and the distribution of collagen, as well as changes in elastin and glycosaminoglycans (GAGs). This will answer: 1) Is there an increase in collagen synthesis and/or a change in collagen types in experimentally created mitral regurgitation? 2) Is there a difference in collagen synthesis, collagen types or collagen distribution due to the mechanism of regurgitation? and 3) Is there a concurrent increase in the other structural components of the valve (elastin and glycosaminoglycans (GAGs)) due to regurgitation. In Part Two, the applicants proposed to assess whether the structural change is accompanied by changes in the mechanical properties of mitral valve tissue. The sheep model will be repeated, and in addition human valves will be obtained from explanted hearts from transplant recipients. The biaxial mechanical properties of both will be determined, as well as the collagen orientation to answer: 4) How do the microstructural changes alter the mechanical properties of the valve tissue? 5) Do the pathologic changes seen in human valves parallel either of the experimental models? Finally, in Part Three, the applicants proposed to determine the effect of structural and mechanical property changes on valve function. A three dimensional finite element model will be used which will incorporate the data obtained in Parts One and Two, to answer: (6) Do the microstructural and mechanical property changes significantly alter valve function as tested in a finite element computer model of the mitral valve? 7) Should clinical management of mitral valve disease be altered?